The incidence of HIV-related pulmonary hypertension has been recognized in the last few years with increasing frequency. However, the etiology and underlying molecular mechanisms of this serious complication are unknown. Recent clinical reports indicate that highly active antiretroviral therapy (HAART) may increase the incidence of HIV-related pulmonary hypertension. Our preliminary data have demonstrated that some HAART drugs impaired endothelium-dependent vasorelaxation, reduced the expression of endothelial nitric oxide synthase (eNOS), and increased super oxide anion production in porcine pulmonary arteries in vitro. In addition, some HAART drugs increased endothelial permeability and oxidative stress, and decreased the expression of several junctional molecules inhuman pulmonary artery endothelial cells (HPAECs). Furthetntore, ginsenoside Rbl and ginkgolide A effectively blocked some HAART drug-induced endothelial dysfunction. Based on these studies, we have developed our central hypotheses that some HAART drugs may cause endothelial dysfunction and oxidative stress in pulmonary arteries through unique molecular pathways, and ginseng and ginkgo compounds may effectively block these detrimental effects of HAART drugs on pulmonary arteries. Thus, we propose a multidisciplinary study to test these central hypotheses. Four specific aims are proposed. Aim 1 is designed to determine the effect of HAART drugs on vasomotor activities and the eNOS system in porcine pulmonary arteries and human pulmonary artery endothelial cells. We will investigate the vasomotor activities, eNOS expression, signal transduction pathways, and prostaglandin and endothelin systems. Aim 2 is designed to determine the effect of HAART drugs on endothelial permeability, junction structures, and molecules in human pulmonary artery endothelial cells. We will investigate endothelial permeability, junction molecular expression, and regulation as well as signal transduction pathways. Aim 3 is designed to determine the effect of HAART drugs on the reactive oxygen species (ROS) system in porcine pulmonary arteries and human pulmonary artery endothelial cells. We will investigate the types and molecular sources of ROS production, the activities and gene expression of ROS-generating and internal antioxidant enzymes. Aim 4 is designed to determine the effect of ginseng and ginkgo compounds on HAART drug induced-endothelial dysfunction and oxidative stress in porcine pulmonary arteries and human pulmonary artery endothelial cells. We will study whether ginseng and ginkgo compounds can block some HAART drug-induced vasomotor dysfunction and permeability increase as well as oxidative stress and related gene expression and regulation. The differences of ginseng and ginkgo compounds will be compared with vitamins C and E in blocking HAART-induced endothelial dysfunction. This study will elucidate the molecular mechanisms of HAART drugs' action on pulmonary endothelial cells and provide valuable information for the development of effective strategies for the prevention and treatment of HIV-related pulmonary hypertension.